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1. AI-based histopathology image analysis reveals a distinct subset of endometrial cancers

Author

Amirali Darbandsari, Hossein Farahani, Maryam Asadi, Matthew Wiens, Dawn Cochrane, Ali Khajegili Mirabadi, Amy Jamieson, David Farnell, Pouya Ahmadvand, Maxwell Douglas, Samuel Leung, Purang Abolmaesumi, Steven J. M. Jones, Aline Talhouk, Stefan Kommoss, C. Blake Gilks, David G. Huntsman, Naveena Singh, Jessica N. McAlpine, and Ali Bashashati

Subjects
Science
Abstract

Abstract Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employ artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identify a sub-group of NSMP EC patients that has markedly inferior progression-free and disease-specific survival (termed ‘p53abn-like NSMP’), in a discovery cohort of 368 patients and two independent validation cohorts of 290 and 614 from other centers. Shallow whole genome sequencing reveals a higher burden of copy number abnormalities in the ‘p53abn-like NSMP’ group compared to NSMP, suggesting that this group is biologically distinct compared to other NSMP ECs. Our work demonstrates the power of AI to detect prognostically different and otherwise unrecognizable subsets of EC where conventional and standard molecular or pathologic criteria fall short, refining image-based tumor classification. This study’s findings are applicable exclusively to females.

Published
2024
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2. Person-Generated Health Data in Women’s Health: Scoping Review

Author

Jalisa Lynn Karim, Rachel Wan, Rhea S Tabet, Derek S Chiu, and Aline Talhouk

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundThe increased pervasiveness of digital health technology is producing large amounts of person-generated health data (PGHD). These data can empower people to monitor their health to promote prevention and management of disease. Women make up one of the largest groups of consumers of digital self-tracking technology. ObjectiveIn this scoping review, we aimed to (1) identify the different areas of women’s health monitored using PGHD from connected health devices, (2) explore personal metrics collected through these technologies, and (3) synthesize facilitators of and barriers to women’s adoption and use of connected health devices. MethodsFollowing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for scoping reviews, we searched 5 databases for articles published between January 1, 2015, and February 29, 2020. Papers were included if they targeted women or female individuals and incorporated digital health tools that collected PGHD outside a clinical setting. ResultsWe included a total of 406 papers in this review. Articles on the use of PGHD for women steadily increased from 2015 to 2020. The health areas that the articles focused on spanned several topics, with pregnancy and the postpartum period being the most prevalent followed by cancer. Types of digital health used to collect PGHD included mobile apps, wearables, websites, the Internet of Things or smart devices, 2-way messaging, interactive voice response, and implantable devices. A thematic analysis of 41.4% (168/406) of the papers revealed 6 themes regarding facilitators of and barriers to women’s use of digital health technology for collecting PGHD: (1) accessibility and connectivity, (2) design and functionality, (3) accuracy and credibility, (4) audience and adoption, (5) impact on community and health service, and (6) impact on health and behavior. ConclusionsLeading up to the COVID-19 pandemic, the adoption of digital health tools to address women’s health concerns was on a steady rise. The prominence of tools related to pregnancy and the postpartum period reflects the strong focus on reproductive health in women’s health research and highlights opportunities for digital technology development in other women’s health topics. Digital health technology was most acceptable when it was relevant to the target audience, was seen as user-friendly, and considered women’s personalization preferences while also ensuring accuracy of measurements and credibility of information. The integration of digital technologies into clinical care will continue to evolve, and factors such as liability and health care provider workload need to be considered. While acknowledging the diversity of individual needs, the use of PGHD can positively impact the self-care management of numerous women’s health journeys. The COVID-19 pandemic has ushered in increased adoption and acceptance of digital health technology. This study could serve as a baseline comparison for how this field has evolved as a result. International Registered Report Identifier (IRRID)RR2-10.2196/26110

Published
2024
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3. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author

Martin Köbel, Eun‐Young Kang, Ashley Weir, Peter F Rambau, Cheng‐Han Lee, Gregg S Nelson, Prafull Ghatage, Nicola S Meagher, Marjorie J Riggan, Jennifer Alsop, Michael S Anglesio, Matthias W Beckmann, Christiani Bisinotto, Michelle Boisen, Jessica Boros, Alison H Brand, Angela Brooks‐Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney‐Brooks, Kara L Cushing‐Haugen, Cezary Cybulski, Suha Deen, Mona A El‐Bahrawy, Esther Elishaev, Ramona Erber, Sian Fereday, AOCS Group, Anna Fischer, Simon A Gayther, Arantzazu Barquin‐Garcia, Aleksandra Gentry‐Maharaj, C Blake Gilks, Helena Gronwald, Marcel Grube, Paul R Harnett, Holly R Harris, Andreas D Hartkopf, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Yajue Huang, Anna Jakubowska, Mercedes Jimenez‐Linan, Michael E Jones, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Jaime Lesnock, Jenny Lester, Jan Lubiński, Teri A Longacre, Maria Lycke, Constantina Mateoiu, Bryan M McCauley, Valerie McGuire, Britta Ney, Alexander Olawaiye, Sandra Orsulic, Ana Osorio, Luis Paz‐Ares, Teresa Ramón y Cajal, Joseph H Rothstein, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, Naveena Singh, Helen Steed, Sarah J Storr, Aline Talhouk, Nadia Traficante, Chen Wang, Alice S Whittemore, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Javier Benitez, Andrew Berchuck, David D Bowtell, Francisco J Candido dos Reis, Ian Campbell, Linda S Cook, Anna DeFazio, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Marc T Goodman, Ellen L Goode, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Stefan Kommoss, Nhu D Le, Stewart G Martin, Usha Menon, Francesmary Modugno, Paul DP Pharoah, Joellen M Schildkraut, Weiva Sieh, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Susan J Ramus, and James D Brenton

Subjects
ovarian cancer, high‐grade serous carcinoma, endometrioid, clear cell, TP53, p53, Pathology, RB1-214
Abstract

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Published
2023
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4. Spatial expression of the FGFR2b splice isoform and its prognostic significance in endometrioid endometrial carcinoma

Author

Asmerom T Sengal, Deborah Smith, Cameron E Snell, Samuel Leung, Aline Talhouk, Elizabeth D Williams, Jessica N McAlpine, and Pamela M Pollock

Subjects
alternative splicing, biomarkers, endometrial carcinoma, uterine cancer, endometrial hyperplasia, FGFR2b isoform, Pathology, RB1-214
Abstract

Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression‐free survival (PFS), and disease‐specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform‐specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c− expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c− expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145–0.423; log‐rank p

Published
2022
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5. Gynecologic Cancer Risk and Genetics: Informing an Ideal Model of Gynecologic Cancer Prevention

Author

Lauren C. Tindale, Almira Zhantuyakova, Stephanie Lam, Michelle Woo, Janice S. Kwon, Gillian E. Hanley, Bartha Knoppers, Kasmintan A. Schrader, Stuart J. Peacock, Aline Talhouk, Trevor Dummer, Kelly Metcalfe, Nora Pashayan, William D. Foulkes, Ranjit Manchanda, David Huntsman, Gavin Stuart, Jacques Simard, and Lesa Dawson

Subjects
cancer screening, hereditary cancer syndrome, population-based genetic testing, BRCA, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit “Gynecologic Cancer Prevention: Thinking Big, Thinking Differently” in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy.

Published
2022
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6. Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression

Author

Dane Cheasley, Marta Llaurado Fernandez, Martin Köbel, Hannah Kim, Amy Dawson, Joshua Hoenisch, Madison Bittner, Derek S. Chiu, Aline Talhouk, C. Blake Gilks, Madawa W. Jayawardana, Kathleen I. Pishas, Anne-Marie Mes-Masson, Diane Provencher, Abhimanyu Nigam, Neville F. Hacker, Kylie L. Gorringe, Ian G. Campbell, and Mark S. Carey

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score

Published
2022
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7. From biobank and data silos into a data commons: convergence to support translational medicine

Author

Rebecca Asiimwe, Stephanie Lam, Samuel Leung, Shanzhao Wang, Rachel Wan, Anna Tinker, Jessica N. McAlpine, Michelle M. M. Woo, David G. Huntsman, and Aline Talhouk

Subjects
Biobanks, Biospecimens, Biobank-technologies, Precision medicine, Data commons, Laboratory Information Management Systems (LIMS), Medicine
Abstract

Abstract Background To drive translational medicine, modern day biobanks need to integrate with other sources of data (clinical, genomics) to support novel data-intensive research. Currently, vast amounts of research and clinical data remain in silos, held and managed by individual researchers, operating under different standards and governance structures; a framework that impedes sharing and effective use of data. In this article, we describe the journey of British Columbia’s Gynecological Cancer Research Program (OVCARE) in moving a traditional tumour biobank, outcomes unit, and a collection of data silos, into an integrated data commons to support data standardization and resource sharing under collaborative governance, as a means of providing the gynecologic cancer research community in British Columbia access to tissue samples and associated clinical and molecular data from thousands of patients. Results Through several engagements with stakeholders from various research institutions within our research community, we identified priorities and assessed infrastructure needs required to optimize and support data collections, storage and sharing, under three main research domains: (1) biospecimen collections, (2) molecular and genomics data, and (3) clinical data. We further built a governance model and a resource portal to implement protocols and standard operating procedures for seamless collections, management and governance of interoperable data, making genomic, and clinical data available to the broader research community. Conclusions Proper infrastructures for data collection, sharing and governance is a translational research imperative. We have consolidated our data holdings into a data commons, along with standardized operating procedures to meet research and ethics requirements of the gynecologic cancer community in British Columbia. The developed infrastructure brings together, diverse data, computing frameworks, as well as tools and applications for managing, analyzing, and sharing data. Our data commons bridges data access gaps and barriers to precision medicine and approaches for diagnostics, treatment and prevention of gynecological cancers, by providing access to large datasets required for data-intensive science.

Published
2021
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8. Wearable Biosensors in the Workplace: Perceptions and Perspectives

Author

Lauren C. Tindale, Derek Chiu, Nicole Minielly, Viorica Hrincu, Aline Talhouk, and Judy Illes

Subjects
wearable sensor, wearable electronic devices, occupational safety, biosensor, corporate ethics, workplace sensor, Medicine, Public aspects of medicine, RA1-1270, Electronic computers. Computer science, QA75.5-76.95
Abstract

ObjectivesWearable body and brain sensors are permeating the consumer market and are increasingly being considered for workplace applications with the goal of promoting safety, productivity, health, and wellness. However, the monitoring of physiologic signals in real-time prompts concerns about benefit and risk, ownership of such digital data, data transfer privacy, and the discovery and disclosure of signals of possible health significance. Here we explore the perceptions and perspectives of employers and employees about key ethical considerations regarding the potential use of sensors in the workplace.MethodsWe distributed a survey developed and refined based on key research questions and past literature to a wide range and size of industries in British Columbia, Canada. Both employers (potential Implementers) and employees (potential Users) were invited to participate.ResultsWe received 344 survey responses. Most responses were from construction, healthcare, education, government, and utilities sectors. Across genders, industries, and workplace sizes, we found a convergence of opinions on perceived benefit and concern between potential Implementers and potential Users regarding the motivation to use biosensors in the workplace. Potential Implementers and Users also agreed on issues pertaining to safety, privacy, disclosure of findings of possible medical significance, risks, data ownership, data sharing, and transfer of data between workplaces. The greatest variability between potential Users and Implementers pertained to data ownership.ConclusionStrong agreement in the perception of biosensor use in the workplace between potential Implementers and Users reflects shared interest, motivation, and responsibility for their use. The use of sensors is rapidly increasing, and transparency about key use factors–both practical and ethical–is essential to maintain the current and desirable level of solidarity.

Published
2022
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10. Long-term mortality among women with epithelial ovarian cancer: a population-based study in British Columbia, Canada

Author

Nimisha Arora, Aline Talhouk, Jessica N. McAlpine, Michael R. Law, and Gillian E. Hanley

Subjects
Ovarian Cancer, Histotype, Mortality, Survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Objectives Among women with epithelial ovarian cancer (EOC), histotype is one of the major prognostic factors. However, few data are available on histotype- specific survival and mortality estimates among these patients. We therefore examined survival and causes of death among women with EOC by histotype. Methods A population- based cohort including all ovarian cancer patients diagnosed in British Columbia (BC) between 1990 and 2014 was built using population-based administrative datasets. We compared causes of death within histotypes, by age at diagnosis, BRCA status, and time since diagnosis. Results A total of 6975 women were identified as having been diagnosed with EOC between 1990 and 2014 in BC. The most common cause of death among these women was ovarian cancer until 10 years post diagnosis when other causes surpassed ovarian cancer as the leading cause of death. Among women with serous EOCs, ovarian cancer was the leading cause of death 12 years after diagnosis, whereas ovarian cancer was the leading cause of death for 8 years among women with non- serous EOCs. Among women with serous EOCs, ovarian cancer was the leading cause of death for 12 years among younger women ( = 60 years of age, and those with BRCA mutations were more likely to die from ovarian cancer than those without a BRCA mutation. Conclusions Within 10 years from diagnosis, ovarian cancer is the leading cause of death among women diagnosed with EOC.

Published
2018
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11. diceR: an R package for class discovery using an ensemble driven approach

Author

Derek S. Chiu and Aline Talhouk

Subjects
Data mining, Cluster analysis, Ensemble, Consensus, Cancer, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Given a set of features, researchers are often interested in partitioning objects into homogeneous clusters. In health research, cancer research in particular, high-throughput data is collected with the aim of segmenting patients into sub-populations to aid in disease diagnosis, prognosis or response to therapy. Cluster analysis, a class of unsupervised learning techniques, is often used for class discovery. Cluster analysis suffers from some limitations, including the need to select up-front the algorithm to be used as well as the number of clusters to generate, in addition, there may exist several groupings consistent with the data, making it very difficult to validate a final solution. Ensemble clustering is a technique used to mitigate these limitations and facilitate the generalization and reproducibility of findings in new cohorts of patients. Results We introduce diceR (diverse cluster ensemble in R), a software package available on CRAN: https://CRAN.R-project.org/package=diceR Conclusions diceR is designed to provide a set of tools to guide researchers through a general cluster analysis process that relies on minimizing subjective decision-making. Although developed in a biological context, the tools in diceR are data-agnostic and thus can be applied in different contexts.

Published
2018
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12. Single-Patient Molecular Testing with NanoString nCounter Data Using a Reference-Based Strategy for Batch Effect Correction.

Author

Aline Talhouk, Stefan Kommoss, Robertson Mackenzie, Martin Cheung, Samuel Leung, Derek S Chiu, Steve E Kalloger, David G Huntsman, Stephanie Chen, Maria Intermaggio, Jacek Gronwald, Fong C Chan, Susan J Ramus, Christian Steidl, David W Scott, and Michael S Anglesio

Subjects
Medicine, Science
Abstract

A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision. We suggest this strategy may facilitate development of NanoString and similar molecular assays by accelerating prospective validation and clinical uptake of relevant diagnostics.

Published
2016
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13. Molecular subtype stratified outcomes according to adjuvant therapy in endometrial cancer

Author

Amy Jamieson, Jutta Huvila, Samuel Leung, Derek Chiu, Emily F. Thompson, Amy Lum, Mary Kinloch, Limor Helpman, Shannon Salvador, Danielle Vicus, Sarah Kean, Vanessa Samouelian, Katherine Grondin, Julie Irving, Saul Offman, Carlos Parra-Herran, Susie Lau, Stephanie Scott, Marie Plante, Melissa K. McConechy, David G. Huntsman, Aline Talhouk, Stefan Kommoss, C. Blake Gilks, and Jessica N. McAlpine

Subjects
Oncology, Obstetrics and Gynecology
Published
2023
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14. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

Author

Eun-Young, Kang, Ashley, Weir, Nicola S, Meagher, Kyo, Farrington, Gregg S, Nelson, Prafull, Ghatage, Cheng-Han, Lee, Marjorie J, Riggan, Adelyn, Bolithon, Gordana, Popovic, Betty, Leung, Katrina, Tang, Neil, Lambie, Joshua, Millstein, Jennifer, Alsop, Michael S, Anglesio, Beyhan, Ataseven, Ellen, Barlow, Matthias W, Beckmann, Jessica, Berger, Christiani, Bisinotto, Hans, Bösmüller, Jessica, Boros, Alison H, Brand, Angela, Brooks-Wilson, Sara Y, Brucker, Michael E, Carney, Yovanni, Casablanca, Alicia, Cazorla-Jiménez, Paul A, Cohen, Thomas P, Conrads, Linda S, Cook, Penny, Coulson, Madeleine, Courtney-Brooks, Daniel W, Cramer, Philip, Crowe, Julie M, Cunningham, Cezary, Cybulski, Kathleen M, Darcy, Mona A, El-Bahrawy, Esther, Elishaev, Ramona, Erber, Rhonda, Farrell, Sian, Fereday, Anna, Fischer, María J, García, Simon A, Gayther, Aleksandra, Gentry-Maharaj, C Blake, Gilks, Marcel, Grube, Paul R, Harnett, Shariska Petersen, Harrington, Philipp, Harter, Arndt, Hartmann, Jonathan L, Hecht, Sebastian, Heikaus, Alexander, Hein, Florian, Heitz, Joy, Hendley, Brenda Y, Hernandez, Susanna Hernando, Polo, Sabine, Heublein, Akira, Hirasawa, Estrid, Høgdall, Claus K, Høgdall, Hugo M, Horlings, David G, Huntsman, Tomasz, Huzarski, Andrea, Jewell, Mercedes, Jimenez-Linan, Michael E, Jones, Scott H, Kaufmann, Catherine J, Kennedy, Dineo, Khabele, Felix K F, Kommoss, Roy F P M, Kruitwagen, Diether, Lambrechts, Nhu D, Le, Marcin, Lener, Jenny, Lester, Yee, Leung, Anna, Linder, Liselore, Loverix, Jan, Lubiński, Rashna, Madan, G Larry, Maxwell, Francesmary, Modugno, Susan L, Neuhausen, Alexander, Olawaiye, Siel, Olbrecht, Sandra, Orsulic, José, Palacios, Celeste Leigh, Pearce, Malcolm C, Pike, Carmel M, Quinn, Ganendra Raj, Mohan, Cristina, Rodríguez-Antona, Matthias, Ruebner, Andy, Ryan, Stuart G, Salfinger, Naoko, Sasamoto, Joellen M, Schildkraut, Minouk J, Schoemaker, Mitul, Shah, Raghwa, Sharma, Yurii B, Shvetsov, Naveena, Singh, Gabe S, Sonke, Linda, Steele, Colin J R, Stewart, Karin, Sundfeldt, Anthony J, Swerdlow, Aline, Talhouk, Adeline, Tan, Sarah E, Taylor, Kathryn L, Terry, Aleksandra, Tołoczko, Nadia, Traficante, Koen K, Van de Vijver, Maaike A, van der Aa, Toon, Van Gorp, Els, Van Nieuwenhuysen, Lilian, van-Wagensveld, Ignace, Vergote, Robert A, Vierkant, Chen, Wang, Lynne R, Wilkens, Stacey J, Winham, Anna H, Wu, Javier, Benitez, Andrew, Berchuck, Francisco J, Candido Dos Reis, Anna, DeFazio, Peter A, Fasching, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Beth Y, Karlan, Stefan, Kommoss, Usha, Menon, Hans-Peter, Sinn, Annette, Staebler, James D, Brenton, David D, Bowtell, Paul D P, Pharoah, Susan J, Ramus, Martin, Köbel, MUMC+: MA Obstetrie Gynaecologie (3), MUMC+: Vrouw Moeder en Kind Centrum (3), Obstetrie & Gynaecologie, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (6), RS: GROW - R2 - Basic and Translational Cancer Biology, and AOCS Group

Subjects
Cancer Research, ovarian cancer, Oncology, high-grade serous carcinoma, Human medicine, prognosis, CCNE1 amplification, cyclin E1 expression
Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Published
2023

16. Profiling the immune landscape in mucinous ovarian carcinoma

Author

Nicola S. Meagher, Phineas Hamilton, Katy Milne, Shelby Thornton, Bronwyn Harris, Ashley Weir, Jennifer Alsop, Christiani Bisinoto, James D. Brenton, Angela Brooks-Wilson, Derek S. Chiu, Kara L. Cushing-Haugen, Sian Fereday, Dale W. Garsed, Simon A. Gayther, Aleksandra Gentry-Maharaj, Blake Gilks, Mercedes Jimenez-Linan, Catherine J. Kennedy, Nhu D. Le, Anna M. Piskorz, Marjorie J. Riggan, Mitul Shah, Naveena Singh, Aline Talhouk, Martin Widschwendter, David D.L. Bowtell, Francisco J. Candido dos Reis, Linda S. Cook, Renée T. Fortner, María J. García, Holly R. Harris, David G. Huntsman, Anthony N. Karnezis, Martin Köbel, Usha Menon, Paul D.P. Pharoah, Jennifer A. Doherty, Michael S. Anglesio, Malcolm C. Pike, Celeste Leigh Pearce, Michael L. Friedlander, Anna DeFazio, Brad H. Nelson, and Susan J. Ramus

Subjects
Ovarian Neoplasms, Lymphocytes, Tumor-Infiltrating, Oncology, Tumor Microenvironment, Humans, Obstetrics and Gynecology, Female, Forkhead Transcription Factors, Carcinoma, Ovarian Epithelial, CD8-Positive T-Lymphocytes, B7-H1 Antigen
Abstract

Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

Published
2023
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17. Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification

Author

Emily F. Thompson, Jutta Huvila, Amy Jamieson, Samuel Leung, Amy Lum, Saul Offman, Alice Lytwyn, Mona Lisa Sur, Lynn Hoang, Julie Irving, Nicholas van der Westhuizen, Chantale Morin, Cyrille Bicamumpaka, Nazilla Azordegan, François Gougeon, Kaoutar Ennour-Idrissi, Janine Senz, Melissa K. McConechy, Rosalia Aguirre-Hernandez, Victoria Lui, Carolyn Kuo, Cassidy Bell, Taylor Salisbury, James Lawson, Ellen He, Shanzhao Wang, Derek Chiu, Sarah Kean, Vanessa Samouëlian, Shannon Salvador, Walter Gotlieb, Limor Helpman, Stephanie Scott, Christoph Wohlmuth, Danielle Vicus, Marie Plante, Aline Talhouk, David Huntsman, Carlos Parra-Herran, Mary Kinloch, Katherine Grondin, C. Blake Gilks, Jessica N. McAlpine, Jessica McAlpine, Anita Agrawal, Omar Al-Nourhji, Alon Altman, Marcus Bernardini, C. Bicamumpaka, Mark Carey, Blaise Clarke, Nazila Azordegan, Bojana Djordjevic, Laurie Elit, Alex Ferenczy, Sarah Finlayson, Anthony Fyles, Hugo Garneau, France Gauthier, Prafull Ghatage, Blake Gilks, Kathy Han, Hal Hirte, Fleur Huang, Katharina Kieser, Mary Kinlloch, Iwa Kong, Aalok Kumar, Janice Kwon, Sandra Lee, Eric Leung, Helen Mackay, Eve-Lyne Marchand, Justin Mcginnis, Dianne Miller, Gregg Nelson, Manuela Pelmus, Annick Pina, Anna Plotkin, Diane Provencher, Anna Tinker, Alicia Tone, Stephen Welch, Nicholas Westhuizen, and Katarzyna Jerzak

Subjects
Pathology and Forensic Medicine
Published
2022
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18. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author

Ashley, Weir, Eun-Young, Kang, Nicola S, Meagher, Gregg S, Nelson, Prafull, Ghatage, Cheng-Han, Lee, Marjorie J, Riggan, Aleksandra, Gentry-Maharaj, Andy, Ryan, Naveena, Singh, Martin, Widschwendter, Jennifer, Alsop, Michael S, Anglesio, Matthias W, Beckmann, Jessica, Berger, Christiani, Bisinotto, Jessica, Boros, Alison H, Brand, James D, Brenton, Angela, Brooks-Wilson, Michael E, Carney, Julie M, Cunningham, Kara L, Cushing-Haugen, Cezary, Cybulski, Esther, Elishaev, Ramona, Erber, Sian, Fereday, Anna, Fischer, Luis, Paz-Ares, Javier, Gayarre, Blake C, Gilks, Marcel, Grube, Paul R, Harnett, Holly R, Harris, Arndt, Hartmann, Alexander, Hein, Joy, Hendley, Brenda Y, Hernandez, Sabine, Heublein, Yajue, Huang, Tomasz, Huzarski, Anna, Jakubowska, Mercedes, Jimenez-Linan, Catherine J, Kennedy, Felix K F, Kommoss, Jennifer M, Koziak, Bernhard, Kraemer, Nhu D, Le, Jaime, Lesnock, Jenny, Lester, Jan, Lubiński, Janusz, Menkiszak, Britta, Ney, Alexander, Olawaiye, Sandra, Orsulic, Ana, Osorio, Luis, Robles-Díaz, Matthias, Ruebner, Mitul, Shah, Raghwa, Sharma, Yurii B, Shvetsov, Helen, Steed, Aline, Talhouk, Sarah E, Taylor, Nadia, Traficante, Robert A, Vierkant, Chen, Wang, Lynne R, Wilkens, Stacey J, Winham, Javier, Benitez, Andrew, Berchuck, David D, Bowtell, Francisco J, Candido Dos Reis, Linda S, Cook, Anna, DeFazio, Jennifer A, Doherty, Peter A, Fasching, María J, García, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, David G, Huntsman, Beth Y, Karlan, Stefan, Kommoss, Francesmary, Modugno, Joellen M, Schildkraut, Hans-Peter, Sinn, Annette, Staebler, Linda E, Kelemen, Caroline E, Ford, Usha, Menon, Paul D P, Pharoah, Martin, Köbel, and R, Sharma

Subjects
Cancer Research, Oncology
Abstract

Background Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. Methods Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. Results Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67–0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant. Conclusion We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2022
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19. Artificial intelligence-based histopathology image analysis identifies a novel subset of endometrial cancers with distinct genomic features and unfavourable outcome

Author

Amirali Darbandsari, Hossein Farahani, Matthew Wiens, Dawn Cochrane, Amy Jamieson, David Farnell, Pouya Ahmadvand, Maxwell Douglas, Samuel Leung, Purang Abolmaesumi, Steven JM Jones, Aline Talhouk, Stefan Kommoss, C Blake Gilks, David G. Huntsman, Naveena Singh, Jessica N. McAlpine, and Ali Bashashati

Abstract

Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employed artificial intelligence (AI)-powered histopathology image analysis to identify a novel sub-group of NSMP EC patients that had markedly inferior progression free and disease free survival in a discovery cohort of 368 patients and an independent validation cohort of 290 patients from another center. Shallow whole genome sequencing revealed a higher burden of copy number abnormalities in the identified group, compared to other NSMP EC, in our discovery and validation cohorts. Taken together, our work demonstrates the power of AI to discover new knowledge, identifying a prognostically relevant subset of EC that is unrecognizable with conventional histopathological assessment, refining image-based tumor classification.

Published
2023
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21. Supplementary Figure 4 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression

Published
2023
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22. Supplementary Figure 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Figure 1: Methylation Signature Approximation

Published
2023
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23. Supplementary Figure 2 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Figure 2: No Association between Methylation Signature and Baseline Clinical Factors

Published
2023
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24. Supplementary Table 6 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Table 6: Multivariate Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data

Published
2023
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25. Supplementary Figure 3 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Figure 3: Immune Analysis

Published
2023
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26. Supplementary Methods 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature

Published
2023
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27. Supplementary Table 5 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Table 5: Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data, excluding data from Previously Published Participants

Published
2023
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28. Supplementary Table 4 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Table 4: Multivariate Modeling of Methylation Signature Among Studies with Multiple Datatypes

Published
2023
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29. Data from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Background:Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features.Methods:We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1.Results:Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17–3.81; P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66–2.95; P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis.Conclusions:Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment.Impact:This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.

Published
2023
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30. Supplementary Table 2 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach

Published
2023
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31. Supplementary Table 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Ellen L. Goode, Stacey J. Winham, David D. Bowtell, Jesus Gonzalez Bosquet, Tanja Pejovic, Martin Widschwendter, Michael S. Anglesio, Dinuka Ariyaratne, Jennifer A. Doherty, Sian Fereday, Dale W. Garsed, Brooke D. Jorgensen, Martin Köbel, Nadja Pejovic, Susan J. Ramus, Aline Talhouk, Nadia Traficante, Robert A. Vierkant, Sebastian M. Armasu, Bryan M. McCauley, Mark E. Sherman, Julie M. Cunningham, Matthew S. Block, and Chen Wang

Abstract

Supplementary Table 1: Characteristics of Study Participants with High Grade Serous Tubo-Ovarian Carcinoma by Contributing Study

Published
2023
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32. Supplementary Methods 1 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Methods

Published
2023
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33. Supplementary Figures S1-S13 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Figures S1-S13

Published
2023
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34. Supplementary Tables S1-S11 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

Susan J. Ramus, Michael L. Friedlander, Martin Köbel, Anna DeFazio, Lyndal Anderson, Paul D.P. Pharoah, Aline Talhouk, Anna H. Wu, Karin Sundfeldt, Annette Staebler, Sue K. Park, Francesmary Modugno, Gottfried E. Konecny, Stefan Kommoss, Linda E. Kelemen, Beth Y. Karlan, Paul A. James, David G. Huntsman, Estrid Høgdall, Nicholas J. Hawkins, Jacek Gronwald, Peter A. Fasching, Philip Crowe, Paul A. Cohen, Heather Thorne, Rebekka Wiedenhoefer, Robyn L. Ward, Paul Timpson, Katrina Tang, Soseul Sung, Deepak Subramanian, Colin J.R. Stewart, Helen Steed, Mitul Shah, Clare L. Scott, Stuart Salfinger, Matthias Ruebner, Marjorie J. Riggan, Jianyu Rao, Ganendra Raj Mohan, Carmel M. Quinn, Malcolm C. Pike, John V. Pearson, Celeste Leigh Pearce, Sang-Yoon Park, Sandra Orsulic, David Morris, Suzana Mittelstadt, Parham Minoo, Janusz Menkiszak, Simone McInerny, Constantina Mateoiu, Sakshi Mahale, Jan Lubiński, Anna Linder, Belle W.X. Lim, Winston Liauw, Na Li, Yee Leung, Jenny Lester, Angela Laslavic, Tiffany Lai, Jennifer M. Koziak, Kayla Klett, Jae-Hoon Kim, Jae-Weon Kim, Byoung-Gie Kim, Catherine J. Kennedy, Mercedes Jimenez-Linan, Anna Jakubowska, Tomasz Huzarski, Claus K. Høgdall, Anusha Hettiaratchi, Arndt Hartmann, Paul R. Harnett, Marcel Grube, Charlie Gourley, Anthony J. Gill, Blake Gilks, Zhuxuan Fu, Anna Fischer, Rhonda Farrell, Ramona Erber, Esther Elishaev, Cezary Cybulski, Joshua Cohen, Dane Cheasley, Ian Campbell, James D. Brenton, Alison H. Brand, David D.L. Bowtell, Jessica Boros, Matthias W. Beckmann, Ellen Barlow, Jennifer Alsop, Adeline Tan, Angela Chou, Ksenia Chezar, Kara L. Cushing-Haugen, Andrew Berchuck, Joellen M. Schildkraut, Holly R. Harris, Jennifer A. Doherty, Kylie-Ann Mallitt, Michael S. Anglesio, Derek S. Chiu, Chi Nam Ignatius Pang, Adelyn Bolithon, Matthew Wakefield, Kylie L. Gorringe, and Nicola S. Meagher

Abstract

Supplementary Tables S1-S11

Published
2023
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36. Supplementary Data from Endometrial Cancer Molecular Risk Stratification is Equally Prognostic for Endometrioid Ovarian Carcinoma

Author

Michael S. Anglesio, Martin Köbel, Stefan Kommoss, Tjalling Bosse, Annette Staebler, Anna V. Tinker, Naveena Singh, Jessica N. McAlpine, Ali Bashashati, Emily F. Thompson, Marco de Bruyn, Hans W. Nijman, Cornelis D. de Kroon, Ranjit Manchanda, Hans-Walter Vollert, Friedrich Kommoss, Sabine Heublein, Hans-Peter Sinn, Felix K.F. Kommoss, Philipp Harter, Andreas du Bois, Florian Heitz, Sara Brucker, Bernhard Krämer, Andreas Hartkopf, Katherine Dixon, Jana Pasternak, Lukas Feil, Samuel Leung, Janine Senz, Zhouchunyang Xia, Marcel Grube, Tayyebeh M. Nazeran, David Farnell, Rory F.L. Hammond, Daniëlla A. Scheunhage, Evan S. Cairns, Derek S. Chiu, Mary Anne Brett, Aline Talhouk, and Pauline Krämer

Abstract

Package with all supplemental figures and tables

Published
2023
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38. Data from Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

Author

Jessica N. McAlpine, C. Blake Gilks, David G. Huntsman, Cheng-Han Lee, Linda J. Reha-Krantz, Janine Senz, Winnie Yang, Derek Chiu, Samuel Leung, Aline Talhouk, and Melissa K. McConechy

Abstract

Purpose: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed.Experimental Design: A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS.Results:POLEEDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15–0.73] and 0.35 (95% CI, 0.13–0.92), respectively.Conclusions: POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women. Clin Cancer Res; 22(12); 2865–73. ©2016 AACR.

Published
2023
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41. Supplementary Data from Molecular Classification of Epithelial Ovarian Cancer Based on Methylation Profiling: Evidence for Survival Heterogeneity

Author

Nicolas Wentzensen, Mark E. Sherman, Aline Talhouk, Susan J. Ramus, Jennifer A. Doherty, David D.L. Bowtell, Michael S. Anglesio, Jolanta Lissowska, Louise A. Brinton, Rayna Matsuno, William F. Anderson, Joshua N. Sampson, J. Keith Killian, and Clara Bodelon

Abstract

Supplemental Figures and tables

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2023
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42. Data from Molecular Classification of Epithelial Ovarian Cancer Based on Methylation Profiling: Evidence for Survival Heterogeneity

Author

Nicolas Wentzensen, Mark E. Sherman, Aline Talhouk, Susan J. Ramus, Jennifer A. Doherty, David D.L. Bowtell, Michael S. Anglesio, Jolanta Lissowska, Louise A. Brinton, Rayna Matsuno, William F. Anderson, Joshua N. Sampson, J. Keith Killian, and Clara Bodelon

Abstract

Purpose:Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes.Experimental Design:A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC).Results:Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P = 9.1 × 10−7) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P = 0.007).Conclusions:DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer.See related commentary by Ishak et al., p. 5729

Published
2023
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43. Data from Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma

Author

Jessica N. McAlpine, Brad H. Nelson, Michael S. Anglesio, C. Blake Gilks, Katy Milne, Samuel Leung, Pascal Schmidt, Heather Derocher, and Aline Talhouk

Abstract

Purpose:Tumors with high mutation load are thought to engender stronger immune responses, which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TILs) and immunosuppressive factors across the 4 molecular subtypes of endometrial cancer, which have characteristic mutation rates ranging from low to ultra-high.Experimental Design:A total of 460 endometrial cancers were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into 4 molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wild-type (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex IHC and tested for associations with ProMisE subtype, survival, and other clinicopathologic parameters.Results:Two major TIL patterns were observed. TILhigh tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TILlow tumors were generally devoid of immunologic features and were more prevalent in p53abn and p53wt endometrial cancers, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, and TIL clusters, only ProMisE showed independent prognostic significance.Conclusions:Immune response correlates with endometrial cancer molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within endometrial cancer molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy.See related commentary by Mullen and Mutch, p. 2366

Published
2023
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44. Data from Endometrial Cancer Molecular Risk Stratification is Equally Prognostic for Endometrioid Ovarian Carcinoma

Author

Michael S. Anglesio, Martin Köbel, Stefan Kommoss, Tjalling Bosse, Annette Staebler, Anna V. Tinker, Naveena Singh, Jessica N. McAlpine, Ali Bashashati, Emily F. Thompson, Marco de Bruyn, Hans W. Nijman, Cornelis D. de Kroon, Ranjit Manchanda, Hans-Walter Vollert, Friedrich Kommoss, Sabine Heublein, Hans-Peter Sinn, Felix K.F. Kommoss, Philipp Harter, Andreas du Bois, Florian Heitz, Sara Brucker, Bernhard Krämer, Andreas Hartkopf, Katherine Dixon, Jana Pasternak, Lukas Feil, Samuel Leung, Janine Senz, Zhouchunyang Xia, Marcel Grube, Tayyebeh M. Nazeran, David Farnell, Rory F.L. Hammond, Daniëlla A. Scheunhage, Evan S. Cairns, Derek S. Chiu, Mary Anne Brett, Aline Talhouk, and Pauline Krämer

Abstract

Purpose:Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a “one-size-fits-all” approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas–inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC.Experimental Design:IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk POLE mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed.Results:A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes (P < 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis.Conclusions:EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype–specific management recommendations for patients with ENOC; for example, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials.

Published
2023
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48. NACT Supplementary Tables - revised from Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy

Author

Brad H. Nelson, Blaise A. Clarke, Patricia A. Shaw, Kurosh Rahimi, Derek S. Chiu, Aline Talhouk, Katy Milne, David R. Kroeger, Sanaz Sanii, and Charlotte S. Lo

Abstract

Supplementary Table S1. Antibody dilutions used in single-color IHC. Supplementary Table S2. Antibody dilutions and chromogens in multi-color IHC. Supplementary Table S3. Additional patient characteristics of cohort A. Supplementary Table S4. Immune cell densities and absolute counts in matched pre- and post-NACT tumor samples with multiple comparisons (n=26).

Published
2023
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49. NACT Supplementary Figures - revised from Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy

Author

Brad H. Nelson, Blaise A. Clarke, Patricia A. Shaw, Kurosh Rahimi, Derek S. Chiu, Aline Talhouk, Katy Milne, David R. Kroeger, Sanaz Sanii, and Charlotte S. Lo

Abstract

Supplementary Fig. S1. CONSORT diagram of patient selection and cohort construction. Supplementary Fig. S2. Plasma cell infiltrates before and after NACT. The data was generated and analyzed as in Figure 1. Supplementary Fig. S3. Example of intraepithelial PD-1+ FoxP3+ TIL in a quadruple-color IHC of PD-L1 CD8 PD-1 FoxP3. Supplementary Fig. S4. Unsupervised clustering of TIL based on post-NACT data.

Published
2023
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50. Supplemental Appendix from Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

Author

Jessica N. McAlpine, C. Blake Gilks, David G. Huntsman, Cheng-Han Lee, Linda J. Reha-Krantz, Janine Senz, Winnie Yang, Derek Chiu, Samuel Leung, Aline Talhouk, and Melissa K. McConechy

Abstract

Supplemental methods Supplemental Table S1: Clinical characteristics of all POLE mutated and POLE wild-type endometrial carcinomas Supplemental Table S2: Clinical characteristics of POLE mutated and POLE wild-type endometrial carcinomas with association tests Supplemental Table S3: Univariable survival analysis Supplemental Table S4: Multivariable survival analysis for whole cohort Supplemental Table S5: Multivariable survival analysis for grade 3 endometrioid carcinomas only Supplemental Table S6: POLE mutation and treatment interaction analysis Supplemental Table S7: Meta-analysis data extraction and source of multivariable hazard ratios from individual studies Supplemental Table S8: Meta-analysis data extraction and source of multivariable hazard ratios for grade 3 ECs Supplemental Table S9: Computed multivariable hazard ratios of POLE for VGH cohort Supplemental Table S10: Computed multivariable hazard ratios of POLE for Meng cohort Supplemental Table S11: Computed multivariable hazard ratios of POLE for TCGA cohort Supplemental Table S12: Computed multivariable hazard ratios of POLE for grade 3 ECs in VGH cohort Supplemental Table S13: Computed multivariable hazard ratios of POLE for grade 3 ECs in TCGA cohort Supplemental Figure S1A-B: Kaplan Meier plots of OS for the whole EC cohort (A) and grade 3 only (B) Supplemental Figure S2: Kaplan Meier curve for OS of POLE EDM mutated patients and POLE wild-type with and without adjuvant treatment Supplemental Figure S3A-C: Meta-analysis of pooled multivariable hazard ratios for OS of whole cohort (A), DSS for grade 3 only (B), OS for grade 3 only (C)

Published
2023
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